Reproductive outcomes and reproductive health care utilization among male survivors of childhood cancer: A DCCSS-LATER study.

BACKGROUND: Treatment-related gonadal dysfunction leading to fertility problems is a frequently encountered late effect in childhood cancer survivors (CCSs). This study evaluated reproductive outcomes and reproductive health care utilization among male CCSs compared with male siblings. METHODS: A nationwide cohort study was conducted as part of the Dutch Childhood Cancer Survivor LATER study part 1, a questionnaire and linkage study. A questionnaire addressing reproductive outcomes and reproductive health care was completed by 1317 male CCSs and 407 male siblings. A total of 491 CCSs and 185 siblings had a previous or current desire for children and were included in this study. RESULTS: Fewer CCSs had biological children compared with siblings (65% vs. 88%; p < .001). The type of conception by men who fathered a child was comparable between CCSs and siblings (spontaneous conception of 90% of both groups; p = .86). The percentage of men who had consulted a reproductive specialist because of not siring a pregnancy was higher in CCSs compared with siblings (34% vs. 12%; p < .001). Following consultation, fewer CCSs underwent assisted reproductive techniques (ART) compared with siblings (41% vs. 77%; p = .001). After ART, fewer CCSs fathered a child compared with siblings (49% vs. 94%; p = .001). CONCLUSIONS: More male survivors consult a reproductive specialist, but fewer survivors undergo ART and father a child after ART compared with siblings. This insight is important for understanding potential problems faced by survivors regarding family planning and emphasizes the importance of collaboration between oncologists and reproductive specialists.

Different subtypes of chronic fatigue in childhood cancer survivors: A DCCSS LATER study.

INTRODUCTION: The aim of the current study was to investigate whether subtypes of chronic fatigue (CF) can be identified in childhood cancer survivors (CCS), and if so, to determine the characteristics of participants with a specific subtype. METHODS: Participants were included from the nationwide DCCSS LATER cohort. The Checklist Individual Strength (CIS) was completed to assess fatigue. Participants with CF (scored ≥35 on the fatigue severity subscale and indicated to suffer from fatigue for ≥6 months) were divided into subgroups using two-step cluster analysis based on the CIS concentration, motivation, and physical activity subscales. Differences between groups on demographics, psychosocial, lifestyle, and treatment-related variables were determined using ANOVA and chi-square analyses (univariable) and multinomial regression analysis (multivariable). RESULTS: A total of 1910 participants participated in the current study (n = 450 with CF; n = 1460 without CF). Three CF subgroups were identified: Subgroup 1 (n = 133, 29% of participants) had CF with problems in physical activity; Subgroup 2 (n = 111, 25% of participants) had CF with difficulty concentrating; and Subgroup 3 (n = 206, 46% of participants) had multi-dimensional CF. Compared to Subgroup 1, Subgroup 2 more often reported sleep problems, limitations in social functioning, and less often have more than two comorbidities. Subgroup 3 more often reported depression, sleep problems, a lower self-esteem, and limitations in social functioning and a lower educational level compared to Subgroup 1. CONCLUSION: Different subgroups of CCS with CF can be identified based on fatigue dimensions physical activity, motivation and concentration. Results suggest that different intervention strategies, tailored for each subgroup, might be beneficial.

Treatments affecting splenic function as a risk factor for valvular heart disease in Childhood Cancer Survivors: A DCCSS-LATER study.

PURPOSE: Splenectomy might be a risk factor for valvular heart disease (VHD) in adult Hodgkin lymphoma survivors. As this risk is still unclear for childhood cancer survivors (CCS), the aim of this study is to evaluate the association between treatments affecting splenic function (splenectomy and radiotherapy involving the spleen) and VHD in CCS. METHODS: CCS were enrolled from the DCCSS-LATER cohort, consisting of 6,165 five-year CCS diagnosed between 1963 and 2002. Symptomatic VHD, defined as symptoms combined with a diagnostic test indicating VHD, was assessed from questionnaires and validated using medical records. Differences in the cumulative incidence of VHD between CCS who received treatments affecting splenic function and CCS who did not were assessed using the Gray test. Risk factors were analyzed in a multivariable Cox proportional hazards model. RESULTS: The study population consisted of 5,286 CCS, with a median follow-up of 22 years (5-50 years), of whom 59 (1.1%) had a splenectomy and 489 (9.2%) radiotherapy involving the spleen. VHD was present in 21 CCS (0.4%). The cumulative incidence of VHD at the age of 40 years was significantly higher in CCS who received treatments affecting splenic function (2.7%, 95% confidence interval (CI) 0.4%-4.9%) compared with CCS without (0.4%, 95% CI 0.1%-0.7%) (Gray's test, p = 0.003). Splenectomy was significantly associated with VHD in a multivariable analysis (hazard ratio 8.6, 95% CI 3.1-24.1). CONCLUSIONS AND IMPLICATIONS: Splenectomy was associated with VHD. Future research is needed to determine if CCS who had a splenectomy as part of cancer treatment might benefit from screening for VHD.

Patient-reported symptom monitoring: using (big) data to improve supportive care at the macro-, meso-, and micro-levels.

PURPOSE: This paper aims to provide a comprehensive understanding of the need for continued development of symptom monitoring (SM) implementation, utilization, and data usage at the macro-, meso-, and micro-levels. METHODS: Discussions from a patient-reported SM workshop at the MASCC/ISSO 2022 annual meeting were analyzed using a macro-meso-micro analytical framework of cancer care delivery. The workshop categories "initiation and implementation, barriers to adoption and utilization, and data usage" were integrated for each level. RESULTS: At the macro-level, policy development could encourage data sharing and international collaboration, including the exchange of SM methods, supportive care models, and self-management modules. At the meso-level, institutions should adjust clinical workflow and service delivery and promote a thorough technical and clinical integration of SM. At the micro-level, SM should be individualized, with timely feedback for patients, and should foster trust and understanding of AI decision support tools amongst clinicians to improve supportive care. CONCLUSIONS: The workshop reached a consensus among international experts on providing guidance on SM implementation, utilization, and (big) data usage pathways in cancer survivors across the cancer continuum and on macro-meso-micro levels.

Using a modified Delphi procedure to select a PRO-CTCAE-based subset for patient-reported symptomatic toxicity monitoring in rectal cancer patients.

PURPOSE: Standardized patient-reported outcomes (PRO) monitoring during and after rectal cancer treatment provides insight into treatment-related toxicities patients experience and improves health-related quality-of-life as well as overall survival. We aimed to select a subset of the PRO version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) for standardized monitoring of treatment-related symptomatic toxicities in rectal cancer. METHODS: We used a mixed methods approach including a literature review, and semi-structured interviews with health care providers (HCPs) involved in rectal cancer care and rectal cancer patients. Results from literature and interviews were summarized and used in a modified Delphi procedure to select a PRO-CTCAE subset specific for rectal cancer. RESULTS: Twenty-six PRO-CTCAE symptomatic toxicities were identified from literature. Fifteen HCPs from multiple disciplines (medical, radiation and surgical oncology), and a heterogeneous group of fifteen rectal cancer patients treated with chemotherapy and/or radiotherapy and/or surgery, participated in semi-structured interviews. Ten HCPs (67%) and nine patients (90%) participated in the first Delphi round. The final selected PRO-CTCAE core-subset contained 16 symptomatic toxicities: 'diarrhea', 'fecal incontinence', 'constipation','bloating of the abdomen', 'pain in the abdomen', 'vomiting', 'decreased libido', 'pain during vaginal sex', 'ability to achieve and maintain erection', 'fatigue', 'anxiety', 'feeling that nothing could cheer you up', 'urinary incontinence', 'painful urination', 'general pain', and 'hand-foot syndrome'. CONCLUSION: Based on a comprehensive mixed methods study, a PRO-CTCAE subset for standardized treatment-related symptomatic toxicity monitoring in rectal cancer was identified. Assessment of the effectiveness and compliance of symptomatic toxicity monitoring using this subset is recommended.

Moving beyond barriers: a mixed-method study to develop evidence-based strategies to improve implementation of PROMs in clinical oncology care.

PURPOSE: This study aimed to identify feasible, evidence-based strategies to improve the use of Patient-reported outcome measures (PROMs) implemented in clinical oncology practice. METHODS: A mixed-method study involving observations of consultations and semi-structured interviews with patients and healthcare professionals (HCPs) was conducted to identify facilitators and barriers for using PROMs; barriers and facilitators were structured following the Theoretical Domains Framework. For each barrier, evidence-based improvement strategies were selected using the Behaviour Change Techniques Taxonomy v1. Subsequently, improvement strategies were ranked on priority and feasibility by an expert panel of HCPs, information technology professionals, and PROMs implementation specialists, creating an implementation improvement strategy. RESULTS: Ten consultations were observed and 14 interviews conducted. Barriers for implementation included that the electronic health record and PROMs did not align to the individual needs of end users, the HCPs' hesitance to advice patients about health-related quality-of-life issues, and a lack of consensus on which HCPs were responsible for discussing PROMs with patients. Forty-one improvement strategies were identified, of which 25 remained after ranking. These included: redesigning the PROMs dashboard by including patient management advice, enhancing patient support to complete PROMs, and clarifying HCPs' responsibilities for discussing PROMs. Strategies currently considered less feasible were: improving user-friendliness of the patient portal due to technical constraints, aligning PROMs assessment frequency with clinical courses, and using baseline PROMs for early identification of vulnerabilities and supportive care needs. These will be studied in future research. CONCLUSION: Evidence-based improvement strategies to ensure lasting adoption of PROMs in clinical practice were identified.

The burden of persistent symptom diagnoses in primary care patients: a cross-sectional study.

INTRODUCTION: The burden of symptoms is a subjective experience of distress. Little is known on the burden of feeling unwell in patients with persistent symptom diagnoses. The aim of this study was to assess the burden in primary care patients with persistent symptom diagnoses compared to other primary care patients. METHODS: A cross-sectional study was performed in which an online survey was sent to random samples of 889 patients with persistent symptom diagnoses (>1 year) and 443 other primary care patients after a transactional identification in a Dutch primary care data registry. Validated questionnaires were used to assess the severity of symptoms (PHQ-15), Symptom Intensity and Symptom Interference questionnaires, depression (PHQ-9), anxiety (GAD-7), quality of life (SF-12 and EQ-5D-5L)) and social functioning (SPF-ILs). RESULTS: Overall, 243 patients completed the survey: 178 (73.3%) patients in the persistent symptom diagnoses group and 65 (26.7%) patients in the control group. In the persistent group, 65 (36.5%) patients did not have persistent symptom(s) anymore according to the survey response. Patients who still had persistent symptom diagnoses (n = 113, 63.5%) reported significantly more severe somatic symptoms (mean difference = 3.6, [95% CI: 0.24, 4.41]), depression (mean difference = 3.0 [95% CI: 1.24, 3.61]) and anxiety (mean difference = 2.3 [95% CI: 0.28, 3.10]) and significantly lower physical functioning (mean difference = - 6.8 [95% CI: -8.96, -3.92]). CONCLUSION: Patients with persistent symptom diagnoses suffer from high levels of symptoms burden. The burden in patient with persistent symptoms should not be underestimated as awareness of this burden may enhance person-centered care.

Desire for children among male survivors of childhood cancer: A DCCSS LATER study.

BACKGROUND: Knowledge of the desire for children among childhood cancer survivors (CCSs) is scarce. This study evaluated the desire for children in male CCSs in comparison with male siblings. METHODS: A nationwide cohort study was conducted as part of the Dutch Childhood Cancer Survivor Study LATER study: 1317 male CCSs and 407 male sibling controls completed a questionnaire addressing the desire for children. Logistic regression analyses were used to explore the independent association between survivorship status and the desire for children. Furthermore, additional analyses were performed to identify which cancer-related factors were associated with the desire for children in male CCSs. RESULTS: After adjustments for the age at assessment, the percentage of men who had a desire for children was significantly lower among CCSs compared with the siblings (74% vs. 82%; odds ratio [OR], 0.61; 95% CI, 0.46-0.82; p = .001). The association between survivorship status and the desire for children was attenuated after adjustments for marital status, level of education, and employment status (OR, 0.83; 95% CI, 0.61-1.14; p = .250). The percentage of men who had an unfulfilled desire for children remained significantly higher among CCSs compared with the siblings after adjustments for sociodemographic factors (25% vs. 7%; OR, 5.14; 95% CI, 2.48-10.64; p < .001). CONCLUSIONS: The majority of male CCSs have a desire for children. The likelihood of having to deal with an unfulfilled desire for children is 5 times higher among CCSs compared with their siblings. This insight is important for understanding the needs and experienced problems of CCSs regarding family planning and fertility issues.

Quality of Life Is Associated With Survival in Patients With Gastric Cancer: Results From the Randomized CRITICS Trial.

BACKGROUND: The evaluation of health-related quality of life (HRQoL) in clinical trials has become increasingly important because it addresses the impact of treatment from the patient's perspective. The primary aim of this study was to investigate the effect of postoperative chemotherapy and chemoradiotherapy (CRT) after neoadjuvant chemotherapy and surgery with extended (D2) lymphadenectomy on HRQoL in the CRITICS trial. Second, we investigated the potential prognostic value of pretreatment HRQoL on event-free survival (EFS) and overall survival (OS). PATIENTS AND METHODS: Patients in the CRITICS trial were asked to complete HRQoL questionnaires (EORTC Quality-of-Life Questionnaire-Core 30 and Quality-of-Life Questionnaire gastric cancer-specific module) at baseline, after preoperative chemotherapy, after surgery, after postoperative chemotherapy or CRT, and at 12 months follow-up. Patients with at least 1 evaluable questionnaire (645 of 788 randomized patients) were included in the HRQoL analyses. The predefined endpoints included dysphagia, pain, physical functioning, fatigue, and Quality-of-Life Questionnaire-Core 30 summary score. Linear mixed modeling was used to assess differences over time and at each time point. Associations of baseline HRQoL with EFS and OS were investigated using multivariate Cox proportional hazards analyses. RESULTS: At completion of postoperative chemo(radio)therapy, the chemotherapy group had significantly better physical functioning (P=.02; Cohen's effect size = 0.42) and less dysphagia (P=.01; Cohen's effect size = 0.38) compared with the CRT group. At baseline, worse social functioning (hazard ratio [HR], 2.20; 95% CI, 1.36-3.55; P=.001), nausea (HR, 1.89; 95% CI, 1.39-2.56; P<.001), worse WHO performance status (HR, 1.55; 95% CI, 1.13-2.13; P=.007), and histologic subtype (diffuse vs intestinal: HR, 1.94; 95% CI, 1.42-2.67; P<.001; mixed vs intestinal: HR, 2.35; 95% CI, 1.35-4.12; P=.003) were significantly associated with worse EFS and OS. CONCLUSIONS: In the CRITICS trial, the chemotherapy group had significantly better physical functioning and less dysphagia after postoperative treatment. HRQoL scales at baseline were significantly associated with EFS and OS.

Varying severities of symptoms underline the relevance of personalized follow-up care in breast cancer survivors: latent class cluster analyses in a cross-sectional cohort.

PURPOSE: Insights into the severity of co-existing symptoms can help in identifying breast cancer survivors in need of symptom management. We aimed to identify subgroups of breast cancer survivors based on patterns of symptom severity, and characteristics associated with these subgroups. METHODS: We selected surgically treated stage I-III breast cancer survivors 1-5 years post-diagnosis from the Netherlands Cancer Registry (N = 876). We assessed experienced severity of fatigue, nausea, pain, dyspnea, insomnia, appetite, constipation, diarrhea, and emotional and cognitive symptoms through the EORTC-QLQ-C30 Quality of Life Questionnaire on a scale of 0-100. We determined subgroups of survivors using latent class cluster analyses (LCA) based on severity of co-existing symptoms and compared their mean severity to the age-matched female reference population to interpret clinical relevance. We assessed subgroup characteristics by multinomial logistic regression analyses. RESULTS: From 404 respondents (46%), three subgroups of survivors with distinct symptom severity were identified: low severity (n = 116, 28.7%), intermediate severity (n = 224, 55.4%), and high severity (n = 59, 14.6%). The low subgroup reported lower symptom severity than the general population; the intermediate subgroup reported a similar symptom severity, although scores for fatigue, insomnia, and cognitive symptoms were worse (small-medium clinical relevance). The high subgroup had worse symptom severity (medium-large clinical relevance). Compared to the intermediate subgroup, one (RRR: 2.75; CI: 1.22-6.19; p = 0.015) or more (RRR: 9.19; CI: 3.70-22.8; p = < 0.001) comorbidities were significantly associated with the high subgroup. We found no associated treatment characteristics. CONCLUSION: We identified distinct subgroups of breast cancer survivors based on symptom severity, underlining the relevance of further exploring personalized follow-up strategies.

Extrameningeal solitary fibrous tumors-surgery alone or surgery plus perioperative radiotherapy: A retrospective study from the global solitary fibrous tumor initiative in collaboration with the Sarcoma Patients EuroNet.

BACKGROUND: Solitary fibrous tumor (SFT) is a rare mesenchymal malignancy. Although surgery is potentially curative, the local relapse risk is high after marginal resections. Given the lack of prospective clinical trial data, the objective of the current study was to better define the role of perioperative radiotherapy (RT) in various SFT presentations by location. METHODS: This was retrospective study performed across 7 sarcoma centers. Clinical information was retrieved from all adult patients with extrameningeal, primary, localized SFT who were treated between 1990 and 2018 with surgery alone (S) compared with those who also received perioperative RT (S+RT). Differences in treatment characteristics between subgroups were tested using analysis of variance statistics and propensity score matching. Local control and overall survival rates were calculated from the start of treatment until progression or death from any cause. RESULTS: Of all 549 patients, 428 (78%) underwent S, and 121 (22%) underwent S+RT. The median follow-up was 52 months. After correction for mitotic count and surgical margins, S+RT was significantly associated with a lower risk of local progression (hazard ratio, 0.19: P = .029), an observation further confirmed by propensity score matching (P = .012); however, this association did not translate into an overall survival benefit. CONCLUSIONS: The results from this retrospective study investigating perioperative RT in patients with primary extrameningeal SFT suggest that combining RT with surgery in the management of this patient population is significantly associated with a reduced risk of local failures, especially in patients who have less favorable resection margins and in those who have tumors with a high mitotic count.

Quantitative 3T multiparametric MRI of benign and malignant prostatic tissue in patients with and without local recurrent prostate cancer after external-beam radiation therapy.

BACKGROUND: Post-radiotherapy locally recurrent prostate cancer (PCa) patients are candidates for focal salvage treatment. Multiparametric MRI (mp-MRI) is attractive for tumor localization. However, radiotherapy-induced tissue changes complicate image interpretation. To develop focal salvage strategies, accurate tumor localization and distinction from benign tissue is necessary. PURPOSE: To quantitatively characterize radio-recurrent tumor and benign radiation-induced changes using mp-MRI, and investigate which sequences optimize the distinction between tumor and benign surroundings. STUDY TYPE: Prospective case-control. SUBJECTS: Thirty-three patients with biochemical failure after external-beam radiotherapy (cases), 35 patients without post-radiotherapy recurrent disease (controls), and 13 patients with primary PCa (untreated). FIELD STRENGTH/SEQUENCES: 3T; quantitative mp-MRI: T2 -mapping, ADC, and Ktrans and kep maps. ASSESSMENT: Quantitative image-analysis of prostatic regions, within and between cases, controls, and untreated patients. STATISTICAL TESTS: Within-groups: nonparametric Friedman analysis of variance with post-hoc Wilcoxon signed-rank tests; between-groups: Mann-Whitney tests. All with Bonferroni corrections. Generalized linear mixed modeling to ascertain the contribution of each map and location to tumor likelihood. RESULTS: Benign imaging values were comparable between cases and controls (P = 0.15 for ADC in the central gland up to 0.91 for kep in the peripheral zone), both with similarly high peri-urethral Ktrans and kep values (min-1 ) (median [range]: Ktrans = 0.22 [0.14-0.43] and 0.22 [0.14-0.36], P = 0.60, kep = 0.43 [0.24-0.57] and 0.48 [0.32-0.67], P = 0.05). After radiotherapy, benign central gland values were significantly decreased for all maps (P ≤ 0.001) as well as T2 , Ktrans , and kep of benign peripheral zone (all with P ≤ 0.002). All imaging maps distinguished recurrent tumor from benign peripheral zone, but only ADC, Ktrans , and kep were able to distinguish it from benign central gland. Recurrent tumor and peri-urethral Ktrans values were not significantly different (P = 0.81), but kep values were (P < 0.001). Combining all quantitative maps and voxel location resulted in an optimal distinction between tumor and benign voxels. DATA CONCLUSION: Mp-MRI can distinguish recurrent tumor from benign tissue. LEVEL OF EVIDENCE: 2 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:269-278.

Quantitative 3-T multi-parametric MRI and step-section pathology of recurrent prostate cancer patients after radiation therapy.

OBJECTIVES: Diagnosis of radio-recurrent prostate cancer using multi-parametric MRI (mp-MRI) can be challenging due to the presence of radiation effects. We aim to characterize imaging of prostate tissue after radiation therapy (RT), using histopathology as ground truth, and to investigate the visibility of tumor lesions on mp-MRI. METHODS: Tumor delineated histopathology slides from salvage radical prostatectomy patients, primarily treated with RT, were registered to MRI. Median T2-weighted, ADC, Ktrans, and kep values in tumor and other regions were calculated. Two radiologists independently performed mp-MRI-based tumor delineations which were compared with the true pathological extent. General linear mixed-effect modeling was used to establish the contribution of each imaging modality and combinations thereof in distinguishing tumor and benign voxels. RESULTS: Nineteen of the 21 included patients had tumor in the available histopathology slides. Recurrence was predominantly multifocal with large tumor foci seen after external beam radiotherapy, whereas these were small and sparse after low-dose-rate brachytherapy. MRI-based delineations missed small foci and slightly underestimated tumor extent. The combination of T2-weighted, ADC, Ktrans, and kep had the best performance in distinguishing tumor and benign voxels. CONCLUSIONS: Using high-resolution histopathology delineations, the real tumor extent and size were found to be underestimated on MRI. mp-MRI obtained the best performance in identifying tumor voxels. Appropriate margins around the visible tumor-suspected region should be included when designing focal salvage strategies. Recurrent tumor delineation guidelines are warranted. KEY POINTS: • Compared to the use of individual sequences, multi-parametric MRI obtained the best performance in distinguishing recurrent tumor from benign voxels. • Delineations based on mp-MRI miss smaller foci and slightly underestimate tumor volume of local recurrent prostate cancer. • Focal salvage strategies should include appropriate margins around the visible tumor.

Organ-preservation (chemo)radiotherapy for T4 laryngeal and hypopharyngeal cancer: is the effort worth?

PURPOSE: We aimed to analyze the oncological and functional outcomes of chemoradiation for T4 laryngeal and hypopharyngeal cancer. METHODS: Patients treated between 2008 and 2015 with chemoradiation (n = 39) were retrospectively analyzed for oncological and functional (laryngo-esophageal dysfunction-free survival, LED-FS) outcomes and compared with 32 consecutive patients treated primarily with total laryngectomy (TL). LED was scored as event in case of local failure, TL for any reason, persistent tracheotomy and/or feeding tube dependency 2 years after chemoradiation. RESULTS: The 5-year local control (LC) rates in the chemoradiation and TL groups were 64 and 87%, respectively (p = 0.030). The disease-free survival was 54 and 59% (p = 0.810), and overall survival (OS) was 46 and 47% (p = 1.00). In the chemoradiation group, the 5-year cumulative incidence of LED-FS was 46%, but was significantly worse in patients with poor pre-treatment laryngeal function, compared to those without (20% and 74%, respectively, p = 0.001). Furthermore, patients with LED have significantly worse OS compared to those without (32% and 65%, respectively, p = 0.041). Multivariate analysis showed that primary treatment type is significantly predictive for LC, while tumor site and extra-capsular extension were predictive for OS. Poor pre-treatment laryngeal function is the only significant predictive factor for LED. CONCLUSIONS: TL resulted in significantly better LC, as compared to chemoradiation in T4 laryngeal and hypopharyngeal cancer patients and the LED-FS is worse in patients with poor pre-treatment laryngeal function. These patients might benefit more from primary treatment with TL followed by radiotherapy. These issues should be taken into consideration, as patients are counseled about different primary treatment options.

Validation of a model to estimate personalised screening frequency to monitor diabetic retinopathy.

AIMS/HYPOTHESIS: Our study aimed to validate a model to determine a personalised screening frequency for diabetic retinopathy. METHODS: A model calculating a personalised screening interval for monitoring retinopathy based on patients' risk profile was validated using the data of 3,319 type 2 diabetic patients in the Diabetes Care System West-Friesland, the Netherlands. Two-field fundus photographs were graded according to the EURODIAB coding system. Sight-threatening retinopathy (STR) was considered to be grades 3-5. Validity of the model was assessed using calibration and discrimination measures. We compared model-based time of screening with time of STR diagnosis and calculated the differences in the number of fundus photographs using the model compared with those in annual or biennial screening. RESULTS: During a mean of 53 months of follow-up, 76 patients (2.3%) developed STR. Using the model, the mean screening interval was 31 months, leading to a reduced screening frequency of 61% compared with annual screening and 23% compared with biennial screening. STR incidence occurred after a mean of 26 months after the model-based time of screening in 67 patients (88.2%). In nine patients (11.8%), STR had developed before the model-based time of screening. The discriminatory ability of the model was good (C-statistic 0.83; 95% CI 0.74, 0.92). Calibration showed that the model overestimated STR risk. CONCLUSIONS/INTERPRETATION: A large reduction in retinopathy screening was achieved using the model in this population of patients with a very low incidence of retinopathy. Considering the number of potentially missed cases of STR, there is room for improvement in the model. Use of the model for personalised screening may eventually help to reduce healthcare use and costs of diabetes care.

Which patients are at risk of developing symptom diagnoses that persist for more than a year in primary care? Development and external validation of a prediction model.

OBJECTIVES: To train, test and externally validate a prediction model that supports General Practitioners (GPs) in early identification of patients at risk of developing symptom diagnoses that persist for more than a year. METHODS: We retrospectively collected and selected all patients having episodes of symptom diagnoses during the period 2008 and 2021 from the Family Medicine Network (FaMe-Net) database. From this group, we identified symptom diagnoses that last for less than a year and symptom diagnoses that persist for more than a year. Multivariable logistic regression analysis using a backward selection was used to assess which factors were most predictive for developing symptom diagnoses that persist for more than a year. Performance of the model was assessed using calibration and discrimination (AUC) measures. External validation was tested using data between 2018 and 2022 from AHON-registry, a primary care electronic health records data registry including 73 general practices from the north and east regions of the Netherlands and about 460,795 patients. RESULTS: From the included 47,870 patients with a symptom diagnosis in the FaMe-Net registry, 12,481 (26.1%) had a symptom diagnosis that persisted for more than a year. Older age (≥ 75 years: OR = 1.30, 95% CI [1.19, 1.42]), having more previous symptom diagnoses (≥ 3: 1.11, [1.05, 1.17]) and more contacts with the GP over the last 2 years (≥ 10 contacts: 5.32, [4.80, 5.89]) were predictive of symptom diagnoses that persist for more than a year with a marginally acceptable discrimination (AUC 0.70, 95% CI [0.69-0.70]). The external validation showed poor performance with an AUC of 0.64 ([0.63-0.64]). CONCLUSION: A clinical prediction model based on age, number of previous symptom diagnoses and contacts might help the GP to early identify patients developing symptom diagnoses that persist for more than a year. However, the performance of the original model is limited. Hence, the model is not yet ready for a large-scale implementation.

Patient- vs Physician-Initiated Response to Symptom Monitoring and Health-Related Quality of Life: The SYMPRO-Lung Cluster Randomized Trial.

Importance: Online symptom monitoring through patient-reported outcomes can enhance health-related quality of life and survival. However, widespread adoption in clinical care remains limited due to various barriers including the need to reduce health care practitioners' workload. Objective: To report the effects of patient-reported outcome (PRO) symptom monitoring on HRQOL and survival up to 1 year after initiation of any treatment in patients with lung cancer. Design, Setting, and Participants: SYMPRO-Lung is a multicenter stepped-wedge cluster randomized trial including patients with stage I to IV lung cancer. The inclusion period was from October 24, 2019, until September 16, 2021, and data collection ended October 8, 2022. Data analysis was conducted from November 9, 2023, until March 18, 2024. Intervention: Patients in the intervention group reported PRO symptoms weekly using the Patient Reported Outcomes version of the Common Toxicity Criteria for Adverse Events lung cancer subset. If symptoms exceeded a validated threshold, an alert was sent to the health care practitioner (active intervention subgroup) or to the patient (reactive intervention subgroup). Patients in the control group received standard care. Main Outcomes and Measures: Health-related quality of life was measured by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire at baseline, 15 weeks (T1), 6 months (T2), and 1 year (T3), with the summary score (SS) and physical functioning (PF) as primary end points. Linear mixed-effects modeling was used to assess mean differences over time. Effect size (ES) of 0.40 or greater was considered clinically relevant. Cox proportional hazards regression survival analyses were performed to estimate the effect of the intervention on progression-free survival and overall survival (OS). Data were analyzed on an intention-to-treat basis. Results: A total of 515 patients (266 [51.7%] men; mean [SD] age, 65.4 [9.4] years) were included in the study (266 in the control group; 249 in the pooled intervention group). Most baseline characteristics were balanced between groups; however, the most notable exception was the distribution in cancer staging: the intervention group had a higher proportion of patients with stage IV cancer compared with the control group (139 [56%] vs 118 [44%]). The pooled intervention group had a significantly better SS (mean difference T1, 5.22; 95% CI, 2.72-7.73; P < .001; ES = 0.33; mean difference T2, 6.28; 95% CI, 3.65-8.92; P < .001; ES = 0.40; mean difference T3, 3.97; 95% CI, 1.15-6.80; P = .006; ES = 0.25) compared with the control group. Group differences improved more in PF but did not meet the ES greater than or equal to 0.40 threshold (mean difference T1, 7.00; 95% CI, 3.65-10.35; P < .001; ES = 0.27; mean difference T2, 6.79; 95% CI, 3.26-10.31; P < .001; ES = 0.26; mean difference T3, 5.01; 95% CI, 1.23-8.79; P = .009; ES = 0.19). No significant differences in HRQOL were observed between the reactive (n = 89) and active (n = 160) intervention groups. The HR for progression-free survival for the active intervention group compared with the control group was 0.78 (95% CI, 0.58-1.04); the finding was not statistically significant. The HR for overall survival for both interventions groups compared with the control group were not statistically significant.(active: HR, 0.80; 95% CI, 0.55-1.15; reactive: HR, 0.69; 95% CI, 0.42-1.15). Conclusions and Relevance: In this 1-year follow-up of a stepped-wedge cluster randomized trial, PRO symptom monitoring yielded improvements in long-term HRQOL in patients with lung cancer. The reactive approach proved equally effective as the active approach. A nonsignificant potential survival benefit was observed for the intervention group. These positive results provide further evidence for the usefulness of routine PRO symptom monitoring in lung cancer care. Trial Registration: The Netherlands trial register Identifier: NL7897.

Healthcare providers' expected barriers and facilitators to the implementation of person-centered long-term follow-up care for childhood cancer survivors: A PanCareFollowUp study.

BACKGROUND: Childhood cancer survivors face high risks of adverse late health effects. Long-term follow-up care for childhood cancer survivors is crucial to improve their health and quality of life. However, implementation remains a challenge. To support implementation of high-quality long-term follow-up care, we explored expected barriers and facilitators for establishing this follow-up care among healthcare providers from four European clinics. METHODS: A qualitative study was conducted using four focus groups comprising 30 healthcare providers in total. The semi-structured interview guide was developed based on the Grol and Wensing framework. Data was analyzed following a thematic analysis, combining both inductive and deductive approaches to identify barriers and facilitators across the six levels of Grol and Wensing: innovation, professional, patient, social, organizational and economic and political. RESULTS: Most barriers were identified on the organizational level, including insufficient staff, time, capacity and psychosocial support. Other main barriers included limited knowledge of late effects among healthcare providers outside the long-term follow-up care team, inability of some survivors to complete the survivor questionnaire and financial resources. Main facilitators included motivated healthcare providers and survivors, a skilled hospital team, collaborations with important stakeholders like general practitioners, and psychosocial care facilities, utilization of the international collaboration and reporting long-term follow-up care results to convince hospital managers. CONCLUSION: This study identified several factors for successful implementation of long-term follow-up care for childhood cancer survivors. Our findings showed that specific attention should be given to knowledge, capacity, and financial issues, along with addressing psychosocial issues of survivors.

Patients' Characteristics and General Practitioners' Management of Patients with Symptom Diagnoses.

INTRODUCTION: Symptom diagnoses are diagnoses used in primary care when the relevant diagnostic criteria of a disease are not fulfilled. Although symptom diagnoses often get resolved spontaneously without a clearly defined illness nor treatment, up to 38% of these symptoms persist more than 1 year. It is largely unknown how often symptom diagnoses occur, which symptoms persist, and how general practitioners (GPs) manage them. AIM: Explore morbidity rates, characteristics and management of patients with nonpersistent (≤1 year) and persistent (>1 year) symptom diagnoses. METHODS: A retrospective cohort study was performed in a Dutch practice-based research network including 28,590 registered patients. We selected symptom diagnosis episodes with at least 1 contact in 2018. We performed descriptive statistics, Student's T and χ2 tests to summarize and compare patients' characteristics and GP management strategies in the nonpersistent and persistent groups. RESULTS: The incidence rate of symptom diagnoses was 767 episodes per 1000 patient-years. The prevalence rate was 485 patients per 1000 patient-years. Out of the patients who had a contact with their GPs, 58% had at least 1 symptom diagnosis, from which 16% were persistent (>1 year). In the persistent group, we found significantly more females (64% vs 57%), older patients (mean: 49 vs 36 years of age), patients with more comorbidities (71% vs 49%), psychological (17% vs 12%) and social (8% vs 5%) problems. Prescriptions (62% vs 23%) and referral (62.7% vs 30.6%) rates were significantly higher in persistent symptom episodes. CONCLUSION: Symptom diagnoses are highly prevalent (58%) of which a considerable part (16%) persists more than a year.